Prolinamides proline

L-proline and L-prolinamide, respectively. In both cases, the remaining (/ ru,5)-8 is free to catalyze the asymmetric Diels-Alder reaction. 

In direct nitroso aldol reactions of a-branched aldehydes, an L-prolinamide (50) catalyses to give a-hydroxyamino carbonyl compounds which are otherwise dis- favoured ees up to 64% were found.149 Another prolinamide derivative gives similar results in a nitrosobenzene reaction.150 For proline-catalysed cases involving highly substituted cyclohexanones, DFT calculations have highlighted the roles of electro- static and dipole-dipole interactions in the level of de achieved.151 (g)... 

The leaves of Arnica montana L. contain a new alkaloid, N-ethoxycarbonyl-L-prolinamide (1). Its structure has been established by mass, i.r., and n.m.r. spectral analysis, and confirmed by synthesis from L-proline by conversion into the amide followed by reaction with ethyl chloroformate. The synthesis also settles the absolute configuration of the new alkaloid.3... 

By using of a modified proline, L-prolinamide 47 (which is known to be a more reactive catalyst than L-proline in cross-aldol reactions [80]), the enantioselectivity of the direct aldol reactions in ionic liquid [bmim][BF4] was remarkably increased as compared with the reaction carried out in acetone (69% ee) (Scheme 7.26) [81]. However, the reusability of the recovered 47 when immobilized in the ionic liquid layer was somewhat inferior to that of the L-proline catalyst this effect could be ascribed to the increased solubility of the organocatalyst 47 in the extracting organic solvents (not provided in the literature), leading to an increased leaching of the catalyst. 

Ellman and coworkers have shown that chiral sulfinate 14 can catalyse asymmetric aldol reactions of acetone, whereas proline itself gave poor results. However, more active and selective catalysts are prolinamides with general structure 16 containing two or more stereocentres in the molecule, and based on ot-alkylbenzylamines ISa," chiral (3-amino alcohols (16b-d, 16e-f, axially chiral amino hydroxyl-2,2 -binaphtyl amide 16i, ... 

Owing to the increased acidity of an NH group of thioamide relative to the parent amide, proline-thioamide 25a behaves as an excellent catalyst. It has been demonstrated that the reaction occurs in a biphasic medium. Najera" and Li independently synthesised thioamides 25b and 25c,d for enantioselective direct aldol reactions. These ligands were found to be better alternatives to L-prolinamides and provided excellent levels of enantio-seiectivity as compared to their parent ligands. 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

Heterofunctionalisation of carbonyl compounds in the a-position has become an important facet of oiganocatalytic enamine-mediated reactions. In 2005, the Jorgensen group described asymmetric a-sulfenylation of aliphatic aldehydes using TMS-protected prolinol catalysts. The best sulfenylating agent was M-benzylsulfanyl-1,2,4-triazole. Other catalysts, such as proline, prolinol, prolinamide or other secondary amide were less effective. The catalyst with bulkier aromatic groups (C2a) afforded the most enantioselective reaction (Scheme 8.39). 

In 2006 Palomo and coworkers tested several prolinamides in the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes. Hydroxy-proline-derived amides 13 were found to be the most active catalysts for this transformation, establishing the importance of the hydrojy group not only for reaction stereocontrol, but also for catalyst activity. However, 3-hydro>y-prolinamide 13b gave less satisfactory results in terms of stereocontrol, compared to the 4-hydro>y-prolinamide analogue 13a (Scheme 11.11). 

Prolinamides are probably the most large group of (5)-proline (1) derivatives used in the intermolecular aldol reaction, due to their easy preparation, stability of the amide linkage and the enough acidity of the NH-moiety able to activate electrophiles by hydrogen bonding. 

The attachment of proline and proline derivatives to dendrons was a further strategy used to attempt their recycling (Fig. 4.37). Thus, compact and expanded dendrimers functionalized with prolinamide units at the periphery such as system 189 were used in the aldol reaction of cyclopentanone and cyclohexanone with p-nitrobenzaldehyde, with a possible dendritic effect that inaeased the stereoselectivities observed with simple A -benzylproUnamide and G1 dendron 189 [271]. 

Aldol additions of acetone (1) as a nucleophile to ketones without a-acidic protons are feasible. The proline-catalyzed aldol reaction between acetone (1) and 1-aryl-2,2,2-trifluoroethanone (128) led to tertiary alcohol 129 in good yield but with low stereoselectivity [146]. A proline-derived sulfonamide 130 performs much better (Table 3.10, entry 2). Kokotos prepared a prolinamide-thiourea catalyst 131, which under optimum conditions can be used in 2 mol%, even at 0°C (entry 3) [ 147], With proline, the reaction was completed within hours, while more stereoselective catalysts 130 and 131 required 2 days. So far, these are the catalysts of choice for this tran ormation [146-148]. 

A simple trifunctional L-prolinamide (48) based on 8-aminoquinoline catalyses enantioselective aldols of aromatic and aliphatic aldehydes with acetone. L-Proline-anilide (49) is a simple and cheap organocatalyst of direct aldols, giving y e Aldelee up to 99/98/99% in large-scale reactions, and is readily recoverable and reusable. Proline anthranilamide-based pseudopeptides act as bifunctional catalysts for direct aldols, giving good yields and detee up to 99/96%. ... 

Four new benzamido-functionalized prolinamides act as organocatalysts for aldols of aldehydes and cyclic ketones in water, with de/ee up to 96/98%, suggesting that while lateral amide functionality facilitates selectivity in water, introduction of additional chirality into prolines is not essential. ... 

Najera el al. have demonstrated that L-prolinethioamides were more effective catalysts for the asymmetric aldolisation of ketones with aldehydes than the corresponding L-prolinamides under solvent-free conditions. " Thus, the use of a novel recyclable L-prolinethioamide, derived from L-proline and (7 )-l-aminoindane, allowed a wide range of chiral aldol adducts to be obtained with a combination of excellent yields and stereoselectivities in general, and at a low catalyst loading of 5 mol % (Scheme 2.24). Furthermore, an intramolecular version of this process could be developed, providing chiral bicyclic diketones with enantioselectivities of up to 88% ee. 

In this context, prolinamide 2 [5-8] and its aryl-substituted homologs such as 3-5 have been developed [9-14]. Analogous to these examples, binaphthyldiamine-derived compounds such as 6 and 7 have been introduced for use in aqueous systems and as recoverable catalysts [15-18]. For example, Benaglia and coworkers reported that the prolinamide catalyst 7 with a UpophiUc side chain showed efficient catalytic activity in water [16b]. Chiral spiro diamine-derived catalysts have also been designed, albeit in moderate enantioselectivity [19]. Owing to the increased acidity of an NH group of thioamide relative to a normal amide, proline-thioamide catalysts such as 8 have been shown to be more effective [20-23]. 

Several other related systems containing a prolinamide or proline-thioamide core have also been reported [36—42]. 

Analogously to these examples, proline-derived peptide catalysts can also efficiently promote Michael addition reactions [97-99]. Prolinamide or prolyl sulfonamide catalysts are also effective for intramolecular Michael addition reactions [100-102]. Recently, Yang and Carter reported a short-cut strategy to construct an all-carbon substituted quaternary carbon stereogenic center on a cyclohexe-none framework via Robinson-type annulation using the 17-type catalyst (Scheme 1.4) [103]. 

Prolinamide derivatives were found to be highly compatible with IL media. Asymmetric aldol reactions catalyzed by proline amide 18 [42], bis-amide 19 [43], or suUbnylated amide 20 [44] could be efficiently carried out in molten salts [bmim]... 

BF4] or [bmim][PF6] (Scheme 22.8). Bis-amide 19-catalyzed aldol reactions performed in [bmimllBFJ required a much lower excess of donor ketone 21 (3 equiv. instead of 30 equiv. in proline-catalyzed reactions) and allowed a synthesis of chiral compounds 22 bearing heterocyclic, prenyl, or metallocene units [43], The improved catalytic performance of prolinamide derivatives in ionic liquids might be due to a stabihzation of the iminium intermediate formed from the ketone and the catalyst or because of the enhanced nucleophilicity of the enamine [42]. Notably, IL dilution with water (1 1 by volume) accelerated the enamine/iminium ion hydrolysis and raised reaction rates and product yields, with the enantioselec-tivity being retained or even becoming somewhat higher than under water-free conditions [45], Furthermore, the catalyst/lL/water system could be easily recycled five times without aldol yield, dr, and ee losses. 

Proposed transition states for 4-substituted proline and prolinamide-catalyzed... 

As briefly discussed above, another approach for the modiflcation of the proline structure is its transformation into a prolinamide bearing an appropriate subshtu-ent. Apart from simple prolinamide, which catalyzed the self-aldol reaction of... 

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